Compositions and methods of use for extracts of magnoliaceae plants

ABSTRACT

The invention relates to compositions and methods for preventing, treating, or managing sleeplessness, restlessness, weight gain including weight gain due to stress or lack of sleep, or all three comprising the administration of a prophylactically and therapeutically effective amount of Magnoliaceae plant or extracts thereof to a mammal in need of such therapy. Preferably the mammal is human and the compositions have comprise at least two compounds selected from magnolol, honokiol, and magnoflorine. Alternatively, the compositions may also comprise about 2% honokiol by weight of the composition.

This application claims the benefit of U.S. Provisional Application No.60/255,402 filed Dec. 15, 2000, which is incorporated by referenceherein in its entirety.

1. INTRODUCTION

The present invention relates to novel methods and compositions for thetreatment, prevention, or management of sleeplessness, restlessness andweight gain. The methods and compositions utilize plants, portionsthereof or extracts therefrom belonging to the Magnoliaceae family. Inaddition, the methods and compositions utilize mixtures of specificsmall molecules extracted from the plants belonging to the familyMagnoliaceae, such as, but not limited to, magnolol, honokiol, andmagnoflorine. The unique compositions of the invention may also comprisevarious amounts of the Magnoliaceae plant, plant extract, plant extractscombined with different amounts of biologically active small moleculesor other therapeutic agents. These compositions are particularly usefulfor the treatment of sleeplessness, restlessness and weight gain inhumans. The invention also encompasses various modes of administrationof the therapeutic extracts or other compositions of the invention.

2. BACKGROUND OF THE INVENTION

The recent growth in sales of natural products labeled as dietarysupplements in the United States has renewed scientific interest in thestudy of the prophylactic and therapeutic effects of multi-componentbotanical products. Unlike single entity pharmaceutical products,botanical products comprise a large number of diverse chemicalconstituents that often act synergistically to exert a desiredbiological effect. The type of extraction process utilized and themanner in which the formulation is standardized have dramatic effects onthe pharmacological activity of the final product. The development ofnew botanical products requires multidisciplinary effort consisting ofexpertise in ethnobotany, natural product chemistry, analyticalchemistry, pharmacology, and natural product extraction.

2.1 Sleeplessness, Restlessness and Weight Control

Sleep is necessary for survival and good health, but why sleep is neededor exactly how it benefits people is not fully understood. Individualrequirements for sleep vary widely; healthy adults may need as few as 4hours or as many as 9 hours of sleep every day. Most people sleep atnight, but many must sleep during the day to accommodate work schedules.This situation often leads to sleep disorders. Most sleep disorders arecommon.

How long a person sleeps and how rested a person feels on waking can beinfluenced by may factors, including excitement or emotional distress.Medications also can play a part; some medications make a person sleepywhile other makes sleeping difficult. Even some food elements ofadditives such as caffeine, strong spices, and monosodium glutamate(MSG) may affect sleep.

Sleep is not a uniform state; it has several distinct stages throughwhich it normally cycles five or six times every night. Sleep progressesfrom stage 1 (the lightest level, during which the sleeper can beawakened easily) to stage 4 (the deepest level, during which waking thesleeper is difficult). In stage 4, the muscles are relaxed, the bloodpressure is at the lowest, and the heart and breathing rates are attheir slowest. Besides these four stages, there is a form of sleepaccompanied by rapid eye movements (REM) and behavioral activity. DuringREM sleep, electrical activity in the brain is unusually high, somewhatresembling that of wakefulness. The eye movement and brain wave changesthat accompany REM sleep can be recorded electrically on anelectroencephalogram (EEG).

In REM sleep, the rate and depth of breathing increase, but the musclesare greatly relaxed more so than during the deepest levels of non-REMsleep. Most dreaming occurs during REM and stage 3 sleep, while mosttalking during sleep, night terrors, and sleepwalking occur duringstages 3 and 4. During a normal night's sleep, REM sleep immediatelyfollows each of the five or six cycles of four-stage non-REM sleep, butit can occur at any of the stages.

If emotional stress is causing the sleep disorder, treatment to relievethe stress is more useful than taking sleep medication. When the sleepdisorder is cause by depression, the depression should be thoroughlyevaluated and treated by a doctor. Some antidepressant drugs can improvesleep because they have sedating properties. When sleep disordersinterfere with a person's normal activities and sense of well-being, theintermittent use of sleep medications (sedatives, hypnotics) may beuseful.

A sedative drug decreases activity, moderates excitement, and calms therecipient, whereas a hypnotic drug produces drowsiness and facilitatesthe onset and maintenance of a state of sleep that resembles naturalsleep in its electroencephalographic characteristics and from which therecipient can be aroused easily. The latter effect sometimes is calledhypnosis.

Nonbenozodiazepine sedative-hypnotic drugs belong to a group of agentsthat depress the central nervous system (CNS) in a relativenonselective, dose-dependent fashion, producing progressively calming ordrowsiness (sedation), sleep (pharmacological hypnosis),unconsciousness, coma, surgical anesthesia, and fatal depression ofrespiration and cardiovascular regulation.

Hypnotics (sedatives, minor tranquilizers, anti-anxiety drugs) are amongthe most commonly used drugs. Most are quite safe, but all can losetheir effectiveness once a person becomes accustomed to them. Anundesirable side effect of hypnotics, however, are the withdrawalsymptoms when use is discontinued. After more than a few days' use,discontinuing a hypnotic can make the original sleep problem worse(rebound insomnia) and increase anxiety. Also most hypnotics require adoctor's prescription because they may be habit-forming or addictive,and overdose is possible. Hypnotics are particularly risky for theelderly and for people with breathing problems because they tend tosuppress brain areas that control breathing. They also reduce daytimealertness, making driving or operating machinery hazardous. Hypnoticsare especially dangerous when taken with alcohol, other hypnotics,narcotics, antihistamines, and anti-depressants. All of these drugscause drowsiness and can suppress breathing, making the combined effectsmore dangerous.

Stress plays a major role in weight management. Stress activates thehypothalamic/pituitary/adrenal axis resulting in an increase in cortisollevels. Cortisol increases the availability of glucose through hepaticgluconeogeneses and the release of glucose substrates from fat cells andmuscles. The uptake of glucose is inhibited, resulting in hyperglycemiaand hyperlipidemia. The increase in cortisol levels signals the brainthat the body is in stress causing food cravings, especially high fat,high sugar foods. These foods, in turn, cause additional stress therebyfueling the stress-cortisol cycle. Eventually, more fat is stored thanthe body needs unless sufficient exercise is in place to compensate, orthe stress is reduced. Central nervous stimulants have been used tosuppress appetite in an attempt to counteract stress-induced appetite.This approach not only aggravates the problem due to a direct CNSstimulation effect, but also has a high abuse potential and severalserious side effects including cardiovascular and cerebral vasculareffects. Ephedra, which is also known as ma huang, is a dietarysupplement that is used for weight control and is an example of thistype of approach. The purported mechanism of action for Ephedra is CNSstimulation due to the presence of ephedrine alkaloids in the extract.

2.3 Magnoliaceae Plant Extracts

Extracts from plants belonging to the family Magnoliaceae have been andmay still be used in Chinese herbalism. The bark of Magnolia officinalisRehder et Wilson, “Hou-po” in Chinese, has been used in Chinesetraditional medicine. (Watanabe, K.; Watanabe, H. Y.; Goto, Y.;Yamamoto, N.; Yoshizaki, M.; “Studies on the Active Principles ofMagnolia Bark. Centrally acting Muscle Relaxant Activity of Magnolol andHonokiol,” Japan. J. Pharmacol. 25, 605 (1975)). Magnolol is thebioactive constituent of Magnolia Cortex, the bark of Magnoliaofficinalis, Rehd. Et Wils., Magnoliaceae or of M. obvata, Thunb.,called wakoboku in Japanese medicine. Honokiol is the bioactiveprinciple isolated from the bark of Magnolia obovata, Thunb.,Magnoliaceae and other Magnolia species used in Japanese and Chinesetraditional medicine.

The bark of Magnolia officinalis, is reportedly used as anantibacterial, antiseptic, antispasmodic, aphrodisiac, appetizer,digestive, diuretic, emmenagogue, expectorant, ophthalmic, stomachic,and tonic. (Chevalier, A., The Encyclopedia of Medicinal Plants, DorlingKindersley, London, 1995).

The ether extract of magnolia bark showed a central depressant effectand centrally acting muscle relaxation effect. (Watanabe et al.) Musclerelaxation was shown to be dose-dependent, wherein minimum effectivedoses required at least 90-100 mg/kg, while sedative symptoms wereobserved at lower doses. At large doses, honokiol showed a musclerelaxing effect for 3 hours (250 mg/kg) and produced a loss of rightingreflex (500 mg/kg). (Watanabe et al. p. 606).

In mice, magnolol produced hypomotility, ptosis, and sedation at 63mg/kg when administered intraperitoneally. (Watanabe, K.; Watanabe, H.;Goto, Y.; Yamaguchi, M.; Yamamoto, N.; Hagino, K., “PharmacologicalProperties of Magnolol and Honokiol Extracted from Magnolia officinalis:Central Depressant Effects,” Journal of Medicinal Plant Research: PlantaMedica, 49, pp. 130-108, (1983)). At a dose of 125 mg/kg magnololinduced sedation, ataxia, and prominent muscle relaxation for 2 hr afterinjection. Magnolol at a dose of 250 mg/kg produced an ataxia within 10min, loss of righting reflex in 40 min, and muscle relaxation over 3 hr.Honokiol produced similar effects at doses of 125, 250, and 500 mg/kgi.p. Id.

To date, there are a number of sleep disorders for which there is nodietary supplement available to either prevent or alleviate the disorderor symptoms associated therewith. It is desirable to discover anddevelop dietary supplements or pharmaceutical compositions based uponnatural materials that are both safe and effective. It is particularlydesirable to develop plant extracts for the prevention, treatment, orcontrol of sleeplessness, restlessness and weight gain do to stress orlack of sleep.

3. SUMMARY OF THE INVENTION

The invention described herein encompasses compositions and methods oftreating or preventing sleeplessness, restlessness or weight gainincluding, but not limited to, weight gain due to stress or lack ofsleep. The methods comprise the administration of a therapeutically orprophylactically effective amount of an extract from the Magnoliaceaefamily, particularly to a human in need of such therapy. The plantsbelonging to the Magnoliaceae family include, but are not limited to,plants belonging to the genus Liriodendron and Magnolia. Speciesbelonging to the Liriodendron genus include Liriodendron tulipifera andLiriodendron chinense. Species belonging to the Magnolia genus include,but are not limited to, Magnolia acuminata, Magnolia ashei, Magnoliabiodii, Magnolia cylindrica, Magnolia cambellii, Magnolia denudata,Magnolia fraseri, Magnolia grandiflora, Magnolia hypoleuca, Magnoliakobus, Magnolia liliiflora, Magnolia loegneri, Magnolia macrophylla,Magnolia officinalis, Magnolia pyramidata, Magnolia sargentiana,Magnolia seiboldii, Magnolia soulangiana, Magnolia sprengeri, Magnoliastellata, Magnolia tripetala, Magnolia virginiana, Magnolia zenii, andMichelia figo. The extracts of the invention are prepared using solventssuch as lower alcohols, water, and mixtures thereof.

Preferably, the compositions comprise Magnoliaceae plant extractssoluble in a lower alcohol, water, and mixtures thereof, or at least twocompounds selected from the group consisting of magnolol, honokiol, andmagnoflorine. More preferably, the compositions comprise about 2% ofhonokiol by weight. The compositions may contain a pharmaceuticallyacceptable carrier, excipient, or diluent. The compositions can beincluded as unit dosage suitable for parenteral, oral, or intravenousadministration to a human. Alternatively, the compositions are dietarysupplements, food compositions or beverage compositions suitable forhuman or animal consumption.

The Magnoliaceae plant extract is obtained by cutting or pulverizing aplant of the family Magnoliaceae, extracting the cut or powdered plantparts with a suitable aqueous solvent for a time sufficient to form anextract. Subsequently, the extract is concentrated under reducedpressure and optionally dried. Further, the extract may optionally bepurified to remove undesirable components.

The methods described herein comprise methods for treating, preventing,and managing sleeplessness, restlessness, or both by administering atherapeutically effective amount of a plant extract or a compositioncomprising a Magnoliaceae plant or plant extract, wherein theMagnoliaceae plant belongs to the genus Liriodendron or Magnolia. Themethod of treating the above mentioned conditions includes administeringan extract obtained using a solvent selected from the group consistingof a lower alcohol, water, and mixtures thereof. Alternatively, theextract comprises at least two compounds selected from the groupconsisting of magnolol, honokiol, magnoflorine and pharmaceuticallyacceptable salts thereof. Preferably, the extracts or compositionsthereof comprise at least 2% honokiol by weight, and more preferably 2%honokiol.

3.1 Definitions

As used herein, unless otherwise specified, the term “Magnoliaceaeplant” includes, but is not limited to, any part of a plant within thefamily Magnoliaceae. The plant parts may include plant bodies preferablythe stalk, leaves, fruit or rind, bark, flowers, stems, roots, or seeds.Preferred plants within the Magnoliaceae family are discussed below.

As used herein, unless otherwise specified, the term “treatingsleeplessness” or “treatment of sleeplessness” includes, but is notlimited to, preventing or reducing the disturbances in falling asleep,staying asleep, duration of sleep, or abnormal sleep behaviors.

As used herein, unless otherwise specified, the term “treatingrestlessness”, “treatment of restlessness” or “preventing restlessness”includes, but is not limited to, causing to rest or relax preferablywithout inducing sedation or hypnosis, inducing relaxation withoutinducing muscle relaxation, and relieving nervous tension or stress.Thus, the invention also encompasses methods of inducing relaxationwithout reduction or loss of motor function in humans.

As used herein, unless otherwise specified, the term “managing weightgain” includes, but is not limited to, treating, preventing or reducingweight gain, suppressing appetite and in a preferred embodimenttreating, preventing or reducing weight gain associated with stress orlack of sleep.

As used herein, unless otherwise specified, the term “physiologicallyacceptable carrier,” includes, but is not limited to, a carrier mediumthat does not interfere with the effectiveness of the biologicalactivity of any active ingredients, is chemically inert, and is nottoxic to the consumer or patient to whom it is administered.

As used herein, unless otherwise specified, the term “pharmaceuticallyacceptable salts” refers to salts prepared from pharmaceuticallyacceptable non-toxic acids and bases, including inorganic and organicacids and bases.

As used herein, unless otherwise specified, the term “preventing,”includes, but is not limited to, inhibition or the averting of symptomsassociated with a particular disease or disorder.

As used herein, unless otherwise specified, the term “treating” refersto the administration of the composition after the onset of symptoms ofthe disease or disorder whereas “preventing” refers to theadministration prior to the onset of the symptoms, particularly topatients at risk of the disease or disorder.

As used herein, unless otherwise specified, the term “lower alcohol”includes, but is not limited to, straight chained or branched,substituted or unsubstituted hydrocarbon compounds having at least onehydroxyl group and having one to five carbon atoms. Lower alcoholsinclude, but are not limited to, methanol, ethanol, n-propanol,isopropanol, butanols, and mixtures thereof.

As used herein, unless otherwise specified, the term “obese” includes,but is not limited to, a person having a Body Mass Index (BMI) ofgreater than or equal to about 26.

As used herein, unless otherwise specified, the term “average weight” or“of average weight” includes, but is not limited to, a person having aBody Mass Index (BMI) of less than about 26.

4. DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses methods for preventing, treating, and managingsleeplessness, restlessness, or weight gain including, but not limitedto, weight gain due to lack of sleep comprising the administration of aprophylactically and therapeutically effective amount of Magnoliaceaeplant or an extract thereof to a mammal in need of such therapy. In apreferred embodiment, the mammal is human and the extracts comprise atleast two compounds selected from the group consisting of magnolol,honokiol, and magnoflorine. In a more preferred embodiment, the extractscomprise at least 2% honokiol by weight of the composition andpreferably, 2% honokiol by weight of the composition. In a mostpreferred embodiment the extracts are aqueous or lower alcohol aqueousextracts.

The invention further encompasses compositions for preventing, treating,and managing sleeplessness, restlessness, or weight gain including, butnot limited to, weight gain due to lack of sleep comprising atherapeutically effective amount of Magnoliaceae plant or an extractthereof including, but not limited to, magnolol, honokiol andmagnoflorine.

In one embodiment of the invention, the composition for preventingsleeplessness comprises Magnoliaceae plant or extracts thereof in anamount sufficient to prevent the onset of sleeplessness or sleeplessnessrelated symptoms. In another embodiment of the invention, for mammalsalready suffering from sleeplessness, the invention is directed tocompositions and administered dosages comprising Magnoliaceae plant insufficient amount to reduce sleeplessness or the symptoms associatedwith sleeplessness. In yet another embodiment of the invention, formammals already suffering from sleeplessness, the invention is directedto a method for treating sleeplessness by administering compositionscomprising Magnoliaceae plant extract in a therapeutically sufficientamount to treat sleeplessness.

In another embodiment of the invention, the composition for reducing orpreventing restlessness comprises Magnoliaceae plant or extracts thereofin an amount sufficient to prevent the onset of restlessness orrestlessness related symptoms. In another embodiment of the invention,the composition for treating restlessness is in sufficient amount andregularly administered dosage to reduce or eliminate restlessnessrelated symptoms in mammals suffering from restlessness. In yet anotherembodiment of the invention, for mammals already suffering fromrestlessness, the invention is directed to a method for treatingrestlessness by administering compositions containing Magnoliaceae plantextract in a therapeutically sufficient amount to either prevent ortreat restlessness.

In yet another embodiment, the invention encompasses compositions,including pharmaceutical compositions or dietary supplements, to be usedin managing weight gain including, but not limited to, weight gain dueto stress or lack of sleep. Further, the invention encompasses methodsfor managing weight gain in a mammal which comprises administering amagnoliaceae plant or extract thereof to a mammal in need thereof.

In another embodiment, the invention encompasses methods for managingweight gain in a human, particularly wherein said human is an obese maleor an obese female.

In a further embodiment, the invention encompasses methods for managingweight gain in a human, particularly wherein said human is a male or afemale of average weight.

In still another embodiment, the invention encompasses methods formanaging weight gain in a human, particularly wherein said human is notconcurrently using; has not previously used another dietary supplementor pharmaceutical composition for weight control; or both. The extractsof the invention are particularly useful for humans taking prescriptionmedications for weight gain including, but not limited to, weight gaindue to stress or lack of sleep. The invention, however, encompasses theuse of the extracts in humans before, during, and after treatment withprescription therapies.

More preferably, the Magnoliaceae plant extract is obtained byextracting Magnoliaceae plant parts with a lower alcohol, water, ormixtures thereof. In another preferred embodiment of the invention, thecompositions comprise a Magnoliaceae plant or an extract thereof and anadditional amount of magnolol, honokiol, or magnoflorine in excess toany amount that may be present in the Magnoliaceae plant extract.

The invention encompasses compositions which comprise magnolol,honokiol, magnoflorine, or pharmaceutically acceptable salts thereof andpharmaceutically acceptable excipients, carriers, or diluents. Further,such magnolol, honokiol, magnoflorine compositions can comprisenon-sedating sleep aids or other therapeutic agents. The compositionscomprise magnolol, honokiol, magnoflorine, or a mixture thereof in anamount sufficient and regularly administered dosage to prevent, treat,or manage sleeplessness, restlessness, weight gain due to stress or lackof sleep, or all three.

The disclosure is based, in part, on the discovery that Magnoliaceaeplant or extracts thereof, alone or in combination with other sleepaids, induces relaxation without loss of motor function and restfulsleep. Without being limited by theory, it is believed that Magnoliaceaeplant extracts act synergistically or at least more than additively bybinding to one or more receptor sites to collectively diminish thesymptoms of sleeplessness or restlessness without causing a sedative oraddictive effect.

In a preferred embodiment, the invention encompasses compositions, andthe use thereof, which comprises a water-soluble extract of aMagnoliaceae plant. In a most preferred embodiment, such extracts areproduced by extraction with an aqueous alcohol solvent system such thatthe extracts preferably comprise one or more of the following smallorganic compounds which naturally occur in the plants: magnolol,honokiol, magnoflorine, and the like. It has been discovered that suchextracts have a unique receptor binding affinities despite the fact thatthe extracts are mixtures of components. Thus, the extracts of theinvention have unique benefits in preventing, treating, or managingdisorders. Moreover, the preferred extracts of the invention are usefulfor treating and preventing sleeplessness, restlessness, weight gain dueto stress or lack of sleep, or all three without a sedative or addictiveeffect. Similarly, the extracts of the invention reduce or avoid adverseeffects associated with certain CNS drugs such as physical dependency,withdrawal problems, impaired coordination, loss or reduction of motorfunction, slowed reaction time, sedation, weight gain, constipation, drymouth, confusion, blurred vision, nausea, diarrhea, or headaches.

The extracts of the invention are particularly useful for humans takingprescription medications for sleeplessness, restlessness, or both. Theinvention, however, encompasses the use of the extracts in humansbefore, during, and after treatment with prescription or conventionaltherapies.

In accordance with the present invention, the Magnoliaceae plant can beused alone or in combination with other known therapeutic agents ortechniques to reduce sleeplessness, restlessness, weight gain due tostress or lack of sleep, or all three. Such agents may include vitaminsand minerals, such as magnesium, calcium, or non-sedating sleep aids.

Since novel formulations of Magnoliaceae plant are disclosed herein, theinvention also encompasses methods of using the novel formulations forthe treatment of sleeplessness, restlessness, weight gain due to stressor lack of sleep, or all three in a mammal, wherein the mammal ispreferably a human.

4.1 Method for Obtaining Magnoliaceae Plant Extracts

The plants belonging to the “Magnoliaceae family” used in the presentinvention are plants belonging to the genus Liriodendron and Magnolia.Species belonging to the Liriodendron genus include, but are not limitedto, Liriodendron tulipifera and Liriodendron chinense. Species belongingto the Magnolia genus include, but are not limited to, Magnoliaacuminata, Magnolia ashei, Magnolia biodii, Magnolia cylindrica,Magnolia cambellii, Magnolia denudata, Magnolia fraseri, Magnoliagrandiflora, Magnolia hypoleuca, Magnolia kobus, Magnolia liliiflora,Magnolia loegneri, Magnolia macrophylla, Magnolia officinalis, Magnoliapyramidata, Magnolia sargentiana, Magnolia seiboldii, Magnoliasoulangiana, Magnolia sprengeri, Magnolia stellata, Magnolia tripetala,Magnolia virginiana, Magnolia zenii, and Michelia figo. The mostpreferable plants are Magnolia officinalis and its variants.

The Magnoliaceae plant includes the plant parts as defined above,optionally the plant parts may be cut into small pieces or ground into apowder. Preferably, the plant part includes an extract of theMagnoliaceae plant. During a typical extraction process, theMagnoliaceae plant body, preferably cut into small pieces or ground intoa powder, is placed in a Soxhlet extractor and extracted with anysuitable solvent. Typical solvents include, but are not limited to,water, lower alcohols, or mixtures thereof. Preferably, the solventsused in the extraction include water, ethanol, and mixtures thereof. Thesolvent is maintained at reflux and the Magnoliaceae plant body isextracted for about 8 hours to about 48 hours. Preferably, theMagnoliaceae plant is extracted for about 12 hours to about 40 hours,and more preferably for about 18 hours to about 30 hours.

Subsequently, the solvent is separated and reduced in volume.Optionally, the solvent may be extracted with a second solvent.Thereafter, the extraction solvents are collected and reduced in volumeeither under low pressure or by evaporation to form a residue.Optionally, the residue is diluted and purified by gravitychromatography using at least one suitable solvent easily determined bya skilled artisan with little or no experimentation as the mobile phase.Optionally, the ratio of solvents within the solvent mixture may begradually changed.

An alternative extraction process comprises adding a suitable solvent tothe Magnoliaceae plant body, either grounded into a powder or cut intopieces. The solvents include, but are not limited to water, a loweralcohol, and mixtures thereof. Preferably, the solvents are water,ethanol, or mixtures thereof. The mixture of Magnoliaceae plant andsolvent is allowed to sit overnight, preferably for about 6 hours toabout 40 hours, preferably for about 8 hours to about 18 hours.Subsequently, the mixture is filtered, separating the solids from thefiltrate. The solids are mixed with more solvent and allowed to sitovernight, preferably for about 6 hours to about 40 hours, preferablyfrom about 12 hours to 32 hours, and more preferably from about 8 hoursto about 18 hours. The mixture is separated a second time by filtrationand the filtrates from both extractions are combined, and concentratedunder reduced pressure to obtain a residue. The residue is vacuum driedfor about 1 to about 10 hours, preferably for about 1 to about 2 hoursat room temperature.

Yet another alternative extraction process comprises combining asuitable solvent to the Magnoliaceae plant body, either grounded into apowder or cut into pieces, in a ratio of about 4:1 to about 7:1 byvolume to form a mixture. The mixture is heated to a temperature ofabout 1° F. below the boiling point of the solvent and stirred for aboutan hour. Preferably, if water is used as a solvent, the temperature isabout 212° F. The mixture is filtered and the filtrate is washed withfresh solvent in a volume ratio of about 1:1. Subsequently the filtrateis concentrated under reduced volume and dried in a vacuum oven. In thismethod, suitable solvents include ethanol, methanol, chlorinatedsolvents, propanol, 2-propanol, water, denatured industrial gradealcohol such as SDA-35, and mixtures thereof. Preferably, suitablesolvents include water, ethanol, SDA-35, and mixtures thereof.

4.2 Compositions Comprising Magnoliaceae Plant Extracts and Modes ofAdministration

The invention comprises compositions of Magnoliaceae plant or plantextracts with physiologically suitable carriers including, but notlimited to, pharmaceutical carriers for the treatment of sleeplessness,restlessness, weight gain including, but not limited to, weight gain dueto stress or lack of sleep, or all three. In a preferred embodiment, thecompositions of the present invention comprise at least two compoundsselected from the group consisting of magnolol, honokiol, andmagnoflorine. More preferably, the compositions include at least 2%honokiol by weight of the composition; preferably including 2% honokiolby weight of the composition. Most preferably, the compositions areobtained from the extraction of Magnoliaceae plant parts with an aqueousorganic solution mixture, in particular a water and ethanol solutionmixture, comprising small molecule compounds.

The magnitude of the therapeutic dose of an active ingredient in theacute or chronic management of a disorder or condition will vary withthe severity of the disorder or condition to be treated and the route ofadministration. The dose, and perhaps the dose frequency, will also varyaccording to age, body weight, response, and the past medical history ofthe consumer or patient. Suitable dosing regimens can be readilyselected by those skilled in the art with due consideration of suchfactors.

In one embodiment of the present invention, Magnoliaceae plant comprisesabout 2% to about 100% by weight of the composition. In a preferredembodiment, Magnoliaceae plant comprises about 5% to about 95% by weightof the composition. In a more preferred embodiment, Magnoliaceae plantcomprises about 10% to about 90% by weight of the composition.

In another embodiment of the present invention using Magnoliaceae plantextracts, Magnoliaceae plant extracts comprise about 25% to about 100%by weight of the composition. In a preferred embodiment, Magnoliaceaeplant extracts comprise about 35% to about 90% by weight of thecomposition. In a more preferred embodiment, Magnoliaceae plant extractscomprise about 40% to about 80% by weight of the composition.

In an embodiment, the composition of the invention comprisesMagnoliaceae plant or plant extract present in an amount of about 35% toabout 90% by weight and at least one non-sedating sleep aid.Alternatively, the compositions of the invention can be administeredsequentially or simultaneously in combination with at least onenon-sedating sleep aid.

Magnoliaceae plant or extracts thereof can be formulated using standardformulation techniques into gel caps, teas, tablets, etc. See, e.g.,Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, EastonPa. (1990). Magnoliaceae plant extracts of the invention may beformulated into a dietary supplement or a pharmaceutical preparation forthe administration to mammals for the treatment of sleeplessness,restlessness, weight gain, preferably weight gain due to stress or lackof sleep, or all three. In a preferred embodiment, the mammal is human.

Compositions comprising Magnoliaceae plant extracts of the inventionformulated in a compatible pharmaceutical carrier may be prepared,packaged, and labeled for treatment, prevention, or management ofsleeplessness, restlessness, or symptoms thereof.

If the composition is water-soluble, then it may be formulated in anappropriate buffer, for example, phosphate buffered saline or otherphysiologically compatible solutions. Alternatively, if the resultingcomposition has poor solubility in aqueous solvents, then it may beformulated with a non-ionic surfactant such as Tween or polyethyleneglycol. Thus, the compositions and their physiologically acceptablesolvates may be formulated for administration by inhalation orinsufflation (either through the mouth or the nose), oral, buccal,parenteral, or rectal administration.

For oral administration, the pharmaceutical preparation may be in liquidform, for example, solutions, syrups or suspensions, or may be presentedas a drug product for reconstitution with water or other suitablevehicle before use. Such liquid preparations may be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, orfractionated vegetable oils); and preservatives (e.g., methyl orpropyl-p-hydroxybenzoates or sorbic acid). The pharmaceuticalcompositions may take the form of, for example, tablets or capsulesprepared by conventional means with pharmaceutically acceptableexcipients such as binding agents (e.g., pregelatinized maize starch,polyvinyl pyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.,lactose, microcrystalline cellulose or calcium hydrogen phosphate);lubricants (e.g., magnesium stearate, talc or silica); disintegrants(e.g., potato starch or sodium starch glycolate); or wetting agents(e.g., sodium lauryl sulphate). The tablets may be coated by methodswell-known in the art. In a preferred embodiment, the pharmaceuticalcomposition may take the form of a capsule or powder to be dissolved ina liquid for oral consumption. Preparations for oral administration maybe suitably formulated to give controlled release of the activecompound.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may comprise formulatory agents such assuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form for constitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., comprising conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be a formulated as a sustained and/or timed release formulation.The compositions must be maintained above some minimum therapeutic doseto be effective. Such sustained and/or timed release formulations may beadministered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example, as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt. Liposomes and emulsions are well known examplesof delivery vehicles or carriers for hydrophilic drugs. Common timedand/or controlled release delivery systems include, but are not berestricted to, starches, osmotic pumps, or gelatin micro capsules.

The compositions may, if desired, be presented in a pack or dispenserdevice which may comprise one or more unit dosage forms comprising theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration.

4.3 Dietary Supplements Comprising Magnoliaceae Plant Extract

The compositions of the invention may include food compositions,beverage compositions, over the counter, and dietary supplements. TheMagnoliaceae plant or plant extract may be added to various foods so asto be consumed simultaneously. Preferably, the Magnoliaceae plantextract comprises at least two compounds selected from the groupconsisting of magnolol, honokiol, and magnoflorine. More preferably, theMagnoliaceae plant extract comprises about 2% honokiol by weight of thecomposition. As a food additive, the Magnoliaceae plant or plantextracts of the invention may be used in the same manner as conventionalfood additives, and thus, only needs to be mixed with other componentsto enhance the taste. Taste enhancement includes, but is not limited to,imparting to food a refreshingness, vitality, cleanness, fineness, orbracingness to the inherent taste of the food.

It will be recognized that dietary supplements may not use the sameformulation ingredients or have the same sterile and other FDArequirements as pharmaceutical compositions. The dietary supplements maybe in liquid form, for example, solutions, syrups or suspensions, or maybe in the form of a product for reconstitution with water or any othersuitable liquid before use. Such liquid preparations may be prepared byconventional means such as a tea, health beverage, dietary shake, liquidconcentrate, or liquid soluble tablet, capsule, pill, or powder suchthat the beverage may be prepared by dissolving the liquid solubletablet, capsule, pill, or powder within a liquid and consuming theresulting beverage. Alternatively, the dietary supplements may take theform of tablets or capsules prepared by conventional means andoptionally including other dietary supplements including vitamins,minerals, other herbal supplements, binding agents, fillers, lubricants,disintegrants, or wetting agents, as those discussed above. The tabletsmay be coated by methods well-known in the art. In a preferredembodiment, the dietary supplement may take the form of a capsule orpowder to be dissolved in a liquid for oral consumption.

The magnitude of the dietary dose of an active ingredient in the acuteor chronic management of a disorder or condition will vary with theseverity of the disorder or condition to be treated and the route ofadministration. The dose, and perhaps the dose frequency, will also varyaccording to age, body weight, response, and the past medical history ofthe consumer or patient. Suitable dosing regimens can be readilyselected by those skilled in the art with due consideration of suchfactors.

The amount of Magnoliaceae plant or plant extract in a beverage orincorporated into a food product will depend on the kind of beverage,food and the desired effect. In general, a single serving comprises anamount of about 0.1% to about 50%, preferably of about 0.5% to about 20%of the food composition. More preferably a food product comprisesMagnoliaceae plant or plant extract in an amount of about 1% to about10% by weight of the food composition.

Examples of food include, but are not limited to, confectionery such assweets (candies, jellies, jams, etc.), gums, bean pastes, bakedconfectioneries or molded confectioneries (cookies, biscuits, etc.),steamed confectioneries, cacao or cacao products (chocolates and cocoa),frozen confectioneries (ice cream, ices, etc.), beverages (fruit juice,soft drinks, carbonated beverages), health drinks, health bars, and tea(green tea, black tea, etc.).

4.4 Dosage

The magnitude of a therapeutic or prophylactic dose of Magnoliaceaeplant in the prevention, treatment, or management of sleeplessness,restlessness, weight gain including, but not limited to, weight gain dueto stress or lack of sleep, or all three will vary with the severity ofthe condition of the consumer or patient to be treated and the route ofadministration. The dose, and dose frequency, will also vary accordingto the age, body weight, condition and response of the individualconsumer or patient, and the particular Magnoliaceae plant combinationused. All combinations described in the specification are encompassed astherapeutic, and it is understood that one of skill in the art would beable to determine a proper dosage of particular Magnoliaceae plantcomposition using the parameters provided in the invention.

In general, the total daily dose ranges of the Magnoliaceae plant forthe conditions described herein are generally from about 1 mg/kg toabout 140 mg/kg administered in divided doses administered parenterally,orally, or topically. A preferred total daily dose is from about 7 mg/kgto about 100 mg/kg of the Magnoliaceae plant composition. When aMagnoliaceae plant extract is used, the total daily dose ranges of theMagnoliaceae plant extract for the conditions described herein aregenerally from about 4 mg/kg to about 12.5 mg/kg administered in divideddoses administered parenterally, orally, or topically. A preferred totaldaily dose is from about 5 mg/kg to about 11 mg/kg of the Magnoliaceaeplant extracts.

Alternatively, the daily dose of the Magnoliaceae plant for theconditions described herein are generally from about 100 mg to about 800mg, preferably from about 200 mg to 600 mg, of a 2% honokiolcomposition.

For example, in one embodiment, the daily dose ranges of Magnoliaceaeplant extracts compositions described herein are generally about 7 mgper kg body weight of Magnoliaceae plant extracts composition.Preferably the Magnoliaceae plant extracts formulation of the inventionis given daily until the symptoms cease, followed by two to tenadditional cycles, each lasting about 60 days in duration. When the doseis administered orally, a sustained release formulation can be used sothat a fairly constant level of Magnoliaceae plant extracts is providedover the course of treatment. As the Magnoliaceae plant extracts are notparticularly toxic, the formulation may be administered for as long asnecessary to achieve the desired therapeutic effect.

In the case where an intravenous injection or infusion composition isemployed, a suitable dosage range for use is, e.g., from about 0.01 toabout 150 mg per kg body weight of Magnoliaceae plant extracts daily.

Again, any suitable route of administration may be employed forproviding the consumer or patient with an effective dosage ofMagnoliaceae plant or plant extracts composition of this invention.Dosage forms include tablets, troches, cachet, dispersions, suspensions,solutions, capsules, gel caps, caplets, compressed tablets, sustainedrelease devices, patches, and the like.

The dietary supplements and pharmaceutical compositions of the presentinvention comprise Magnoliaceae plant or plant extracts as the activeingredients, as well as pharmaceutically acceptable salts thereof, andmay also comprise a pharmaceutically acceptable carrier, and optionally,other therapeutic ingredients.

The dietary supplements and pharmaceutical compositions includecompositions suitable for oral and parenteral (including subcutaneous,intramuscular, intrathecal, intravenous, and other injectables) routes,although the most suitable route in any given case will depend on thenature and severity of the condition being treated.

In addition, the Magnoliaceae plant or plant extracts carrier could bedelivered via charged and uncharged matrices used as drug deliverydevices such as cellulose acetate membranes, also through targeteddelivery systems such as liposomes attached to antibodies or specificantigens.

In practical use, Magnoliaceae plant or plant extracts can be combinedas the active ingredient(s) in intimate admixture with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including tablets, capsules, powders, intravenous injections orinfusions). In preparing the compositions for oral dosage form any ofthe usual pharmaceutical media may be employed, e.g., water, glycols,oils, alcohols, flavoring agents, preservatives, coloring agents, andthe like; in the case of oral liquid preparations, e.g., suspensions,solutions, elixirs, liposomes and aerosols; starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like in the case of oral solidpreparations e.g., powders, capsules, and tablets. In preparing thecompositions for parenteral dosage form, such as intravenous injectionor infusion, similar pharmaceutical media may be employed, e.g., water,glycols, oils, buffers, sugar, preservatives, and the like know to thoseskilled in the art. Examples of such parenteral compositions include,but are not limited to Dextrose 5% (w/v), normal saline or othersolutions. The total dose of the Magnoliaceae plant extracts may beadministered in a vial of intravenous fluid, e.g., ranging from about0.7 to about 14 mg per kg body weight of Magnoliaceae plant extracts.The volume of dilution fluid will vary according to the total doseadministered and over the length of the period of time ofadministration.

5. EXAMPLES

Certain embodiments of the invention, as well as certain novel andunexpected advantages of the invention, are illustrated by the followingnon-limiting examples.

5.1 Restful Sleep Activity 5.1.1 Materials and Methods

Using a model study with 50 volunteer participants, an extract of theinvention was tested for its ability to induce restful sleep propertiesas discussed below.

5.1.1.1 Subjects

The study quantified consumers' perceptions and reactions to a dietarysupplement containing Magnoliaceac extract. The study was an open-label,home usage to test the effectiveness of dietary supplements havingMagnoliaceae extract. The study followed 50 respondents between the ageof 30 and 55 using the dietary supplement for two weeks. The typicalsubject had used dietary supplements within the past three months;suffered from mild anxiety or nervousness at least once in the past twomonths or at least six times a year; and had not taken prescriptionmedication for the treatment of mild anxiety or nervousness in the pastyear. Female participants were screened to ensure that they were notpregnant or nursing an infant.

5.1.1.2 Test Materials

The sample developed and screened for sleep inducing activity was ahydroalcoholic extract from the Magnoliaceae family provided in a 200 mgcapsule.

5.1.1.4 Procedure

All participants were asked to measure sample effectiveness by answeringa series of questions directed to particular conditions. Specifically,the participants were asked to monitor whether the composition waseffective to help them relax; reduce occasional nervous tension; gentlysoothe tension; calm the participant when feeling stressed; help controlirritability; help overcome feelings of restlessness; and help theparticipant cope with everyday overwork and fatigue.

Participants self administered the composition in capsule form about 2-3times during the day.

5.1.2 Results

The respondents took the capsules on an average of 2.7 per day mostlyduring the early morning hours before 9 a.m. or during the eveningbetween 5 p.m. and 10 p.m. Of the subjects, 68% felt that thecomposition was overall effective. Of the subjects, 78% felt that thecomposition was highly effective in inducing a state of relaxationwithout feeling drowsiness. Of the subjects, 74% felt that thecomposition induced restful sleep and was non-sedating. Also, of thesubjects 94% did not feel an upset the stomach or thought the sample hadan unpleasant taste.

5.2 Weight Control

Magnoliaceae extracts can be tested for weight control activity by anynumber of means know to those skilled in the art, including, but notlimited to, short term appetite control paradigms on mice using theprotocol in Talpur, N. A., Echard, B. W.; anohar, V; and Preuss, H. G.;“Influence of a combination of herbs on appetite supression and weightloss in rats,” Diabetes, Obesity & Metabolism. 3,3 (2001); or in BrownM.; Bing, C.; King P.; Pickavance L; Heal, D.; and Wilding, J.;“Sibutramine reduces feeding, body fat, and improves insulin resistancein dietary-obese male winstar rats independently of hypothalamicneuropeptide Y,” British Journal of Pharmacology. 138, 8 (2001).

It is to be understood that the present invention is not limited to theembodiments described above, but encompasses any and all embodimentswithin the scope of the following claims.

What is claimed is:
 1. A method for treating or preventing weight gainin a mammal having elevated cortisol levels which comprisesadministering to said mammal an extract of a Magnoliaceae plant, saidplant belonging to a genus selected from the group consisting ofLiriodendron and Magnoliaceae, said extract being administered in anamount effective to attain homeostatic cortisol levels in said mammal.2. The method of claim 1 wherein said elevated cortisol levels of saidmammal are induced by stress.
 3. The method of claim 1 wherein saidelevated cortisol levels of said mammal are induced by lack of sleep. 4.The method of claim 1 wherein the Magnoliaceae plant extract comprisesat least two compounds selected from the group consisting of magnolol,honokiol, and magnoflorine.
 5. The method according to claim 1 whereinthe Magnoliaceae plant extract comprises about 2% of honokiol.
 6. Themethod of claim 1 wherein said method further comprises coadministeringsaid extract with a dietary supplement.
 7. The method of claim 1 whereinsaid method further comprises coadministering said extract with apharmaceutical composition for weight control.
 8. The method of claim 1wherein said extract is administered to a mammal having normal cortisollevels.
 9. The method of claim 1 wherein said mammal is a human.
 10. Themethod of claim 9 wherein said human is a male.
 11. The method of claim9 wherein said human is a female.